Selected novel flavones inhibit the DNA binding or the DNA religation step of eukaryotic topoisomerase I
Selected novel flavones inhibit the DNA binding or the DNA religation step of eukaryotic topoisomerase I
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DOI：
10.1074/jbc.271.4.2262
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发表时间：
1996-01-26
影响因子：
4.8
通讯作者：
Kohrle, J
中科院分区：
文献类型：
--
作者：
Boege, F;Straub, T;Kohrle, J
拓扑异构酶参与DNA代谢的许多方面，例如复制和转录反应。喜树碱能稳定拓扑异构酶I与DNA的共价中间体，是一种有效的抗癌药物，尽管有毒性。在这项研究中，一类新的拓扑异构酶I抑制剂被鉴定出来，并且利用重组人拓扑异构酶I制剂和人HL - 60白血病细胞对它们的作用方式进行了表征。槲皮素及相关的天然黄酮类化合物，如刺槐素、芹菜素、山奈酚和桑色素，抑制拓扑异构酶I催化的DNA重新连接。与喜树碱不同，这些化合物不直接作用于催化中间体，也不干扰DNA裂解。然而，在裂解反应过程中与拓扑异构酶I和DNA形成的三元复合物抑制了后续的DNA重新连接步骤。3,3',4',7 - 四羟基取代的黄酮类化合物最有效地稳定共价拓扑异构酶I - DNA中间体。在人HL - 60细胞中也证实了共价拓扑异构酶I - DNA复合物形成增加。相反，合成的3',5' - 二溴 - 4' - 羟基 - 3 - 甲基黄酮选择性地与未结合DNA的拓扑异构酶I结合，并阻断后续的DNA结合步骤。因此，这些合成的黄酮类化合物能够抵消喜树碱对拓扑异构酶I的作用。黄酮结构6位上庞大的疏水取代基可抑制DNA结合。我们的数据表明，拓扑异构酶I两个半反应的选择性抑制剂可源自黄酮结构。
Topoisomerases are involved in many aspects of DNA metabolism such as replication and transcription reactions. Camptothecins, which stabilize the covalent intermediate of topoisomerase I and DNA are effective, though toxic, drugs for cancer therapy. In this study, a new class of topoisomerase I inhibitors was identified, and their mode of action was characterized using recombinant human topoisomerase I preparations and human HL-60 leukemic cells. Quercetin and the related natural flavones, acacetin, apigenin, kaempferol, and morin, inhibit topoisomerase I-catalyzed DNA religation. In contrast to camptothecin, these compounds do not act directly on the catalytic intermediate and also do not interfere with DNA cleavage. However, formation of a ternary complex with topoisomerase I and DNA during the cleavage reaction inhibits the following DNA religation step. 3,3',4',7-Tetrahydroxy-substituted flavones stabilize the covalent topoisomerase I-DNA intermediate most efficiently. Enhanced formation of covalent topoisomerase I-DNA complexes was also demonstrated in human HL-60 cells. In contrast, synthetic 3',5'-dibromo-4'-hydroxy-3-methylflavones bind selectively to topoisomerase I in its non-DNA-bound form and block the following DNA binding step. As a consequence, these synthetic flavonoids are capable of counteracting topoisomerase I-directed effects of camptothecin. Inhibition of DNA binding is obtained by voluminous hydrophobic substituents in 6-position of the flavone structure. Our data show that selective inhibitors of both half-reactions of topoisomerase I can be derived from the flavone structure.